Sensitive and selective method and device for the detection of trace amounts of a substance

ABSTRACT

A piezoelectric crystal element and a sensor utilizing the same are presented for use in a sensor device for identifying at least one foreign material from environment. The crystal element comprises at least one crystal resonator in the form of an inverted mesa structure, which has a membrane-like region and has a certain resonance frequency value. A surface region of the crystal resonator is modified by reactive molecules of a kind capable of interacting with the foreign material to yield a reaction product that effects a change in the resonance frequency of the crystal resonator from said certain resonance frequency value. This change is indicative of the identity and quantity of the foreign material.

FIELD OF THE INVENTION

[0001] This invention is in the field of mass detection using a coatedpiezoelectric sensor.

BACKGROUND OF THE INVENTION

[0002] In recent years there has been a growing interest in coatedpiezoelectric crystals, not only as highly sensitive and selectivedetector of various air pollutants but also as simple, inexpensive andportable device. The high sensitivity and simple relationship betweenmass and frequency make the quartz crystal microbalance as an ideal toolfor the study of adsorption and as a selective chemical sensor in manyapplications.

[0003] The principle of the detection is that the frequency of vibrationof an oscillating crystal is decreased by the adsorption of a foreignmaterial on its surface. A gaseous pollutant is selectively adsorbed bya coating on the crystal surface, thereby increasing the weight of thecrystal and decreasing the frequency of vibration. The decrease in thefrequency is proportional to the increase in weight due to the presenceof gas adsorbed on the coating according to the following equation:ΔF=K·ΔC. Here, ΔF is the frequency change (Hz), K is a constant whichrefers to the basic frequency of the quartz plate, area coated, and afactor to convert the weight of injected gas (g) into concentration(ppm), and ΔC is concentration (ppm) of sample gas.

[0004] U.S. Pat. No. 3,164,004 teaches that a piezoelectric quartzcrystal coated with a substrate selectively sensitive to changes in theatmospheric environment can serve as a detection device in fluidanalyzers. In general, this discovery is based on the principle that theoscillation of a crystal, both in frequency and amplitude, is in part afunction of its weight. The change in weight of a crystal coated with asubstrate selectively sensitive to a particular contaminant when placedin an environment containing that contaminant is, in turn, at leastpartly a function of the concentration of the contaminant. Therefore,the measurement of the change in oscillation characteristics of a coatedcrystal sensitive to a particular contaminant upon exposure to a givenatmosphere is a direct and highly sensitive measure of the presence andconcentration of that contaminant. Variations of and improvements inthis basic method are shown, inter alia, in the following publicationsU.S. Pat. Nos. 5,177,994; U.S. Pat. No. 5,817,921, and U.S. Pat. No.6,085,576; Japanese Patents Nos. 1244335, and 5187986; European PatentNo. 992768, and “Electronic Nose and Artificial neural Networks”, L. Moyand M. Collins, American Chemical Society, Anal. Chem., 1986, 58, pp.3077-3084; “Piezoelectric Crystal Sensor for the Determination ofFormaldehyde in Air”, Talanta, Vol. 38, No. 5, pp. 541-545, 1991; “OdorSensing System Using Neural Network Pattern Recognition”, ToyosakaMorizi and Takamichi Nakamoto, International Conference on IndustrialElectronics, Control, Instrumentation and Automation, Nov. 9-13, 1992,Marriot Mission Valley, San Diego, USA.

[0005] A sensor has two equally important requirements: sensitivity andselectivity. There are two ways of achieving high selectivity andspecificity towards xenobiotic (non-self) agents as we can learn fromnature: (i) the immune system, in which a unique sensor (i.e. antibody)is being synthesized for any invader (i.e. antigen). This is a verycomplicated mechanism that involves a spontaneous constant synthesis ofnew molecules that are examined to fit the antigen; (ii) the olfactorysystem, in which a huge array of receptors are located in the nose insuch a way that a molecule entering the nose interacts with some of thereceptors; the brain then translates the pattern of the signals to anodor. In this case the odor can be a single molecule or a composition ofseveral different molecules.

[0006] The combination of a number of sensors and a pattern recognitionroutine is known as an “electronic nose”. Using the combination ofchemical sensors, which produce a fingerprint of the vapor or gas, therecognition algorithms can identify and/or quantify the analytes ofinterest. The electronic nose is capable of recognizing unknown chemicalanalytes, odors, and vapors. In practice, an electronic nose ispresented with a substance such as an odor or vapor, and the sensorconverts the input of the substance into a response, such as anelectrical response. The response is then compared to known responsesthat have been stored previously. By comparing the unique chemicalsignature of an unknown substance to “signatures” of known substances,the unknown analyte can be determined. A variety of sensors can be usedin electronic noses that respond to various classes of gases and odors.

[0007] A wide variety of commercial applications are available forelectronic noses including, but not limited to, detection of explosivesor drugs, environmental toxicology, biomedicine, such as microorganismclassification or detection, material quality control, food andagricultural product monitoring, ambient air monitoring, employeeprotection, emissions control, and product quality testing. Referring tothe detection of explosives, a number of laboratory techniques for thedetection of explosives are known, using gas chromatography, massspectrometry, ion mobility spectroscopy, NMR, plasma chromatography andvisible chromatography. While some of these techniques are capable ofppb detection, the detection systems need elaborate techniques foroperation, are usually not portable and simple, and are thus not usefulfor field use.

SUMMARY OF THE INVENTION

[0008] There is a need in the art for a sensing device that is compact,capable of detecting trace amounts of mass of 10⁻¹⁵ g order and evenless, that is useful in a broad variety of applications and can respondaccurately to a broad variety of gases, analytes, odors and fluids.

[0009] The present invention provides a sensing device (also referred toas an electronic-nose device) that is compact and, in certainembodiments, configured to be a handheld device. The device can be usedto measure or identify one or more analytes in a medium such as vapor,liquid or gas.

[0010] The main idea of the present invention is based on the use of apiezoelectric crystal element (such as quartz, ceramics), which, on theone hand, can be manufactured by the existing techniques to be mountablein a sensor device, and, on the other hand, has a sufficiently thin(membrane-like) region, which defines a sensing region of the crystalelement, thereby providing increased sensitivity as compared to theknown sensors.

[0011] The crystal element, according to the present invention, is inthe form of the so-called “inverted mesa structure”, in which arelatively thin membrane-like region (resonator) is surrounded byrelatively thick end regions of the crystal element. A pair ofelectrodes are located on the opposite sides of this membrane-likeregion. The electrodes and/or the membrane-like region have a surfaceregion coated with reactive molecules, thereby presenting a sensingregion of the device electrically excitable by the environment (whichcan be gas or liquid). The reactive coating molecules interact with aforeign material from the environment to yield a reaction product thateffects a change in the resonance frequency of the crystal resonatorfrom a certain resonance frequency value characterizing said crystalresonator.

[0012] The reactive coating molecules are preferably organized in aself-assembled monolayer (SAM) formed on the surface of the electrodesand/or the membrane-like region (i.e. on the surface of a substrate).The monolayer consists of receptor compounds comprising a linker thatconnects said compound to the surface of said substrate, an optionalspacer, a structural element and an active head group.

[0013] There is thus provided according to one aspect of the presentinvention, a piezoelectric crystal element for use in a sensor devicefor identifying at least one foreign material from environment, thecrystal element comprising at least one crystal resonator in the form ofan inverted mesa structure having a membrane-like region, which issubstantially thinner as compared to end portion of the crystalresonator surrounding said membrane-like region and has a certainresonance frequency value, a surface region of said at least one crystalresonator being modified by reactive molecules of a kind capable ofinteracting with said at least one foreign material to yield a reactionproduct that effects a change in the resonance frequency of saidmembrane-like region from said certain resonance frequency value, saidchange being indicative of the identity and quantity of said at leastone foreign material.

[0014] According to another aspect of the present invention, there isprovided a piezoelectric sensor for use in a device for identifying atleast one foreign material from environment, the sensor comprising apiezoelectric crystal element having at least one crystal resonator inthe form of an inverted mesa structure defining a sensing membrane-likeregion which is substantially thinner as compared to end portion of thecrystal resonator surrounding said membrane-like region and has acertain resonance frequency value, and electrodes formed on oppositesides of said sensing membrane-like region, said at least one crystalresonator having a surface region modified with molecules capable ofinteracting with at least one foreign material from the environment towhich the crystal resonator is exposed to yield a reaction product thateffects a change in the resonance frequency of said membrane-like regionfrom said certain resonance frequency value, said change beingindicative of the identity and quantity of said foreign material.

[0015] The input and output of the sensor is connectable to a controlmeans operable for actuating the at least one crystal resonator andmeasuring the change in the resonance frequency, to generate measureddata representative of the identity and quantity of said foreignmaterial.

[0016] The metal electrodes used in the sensor may comprise a metalselected from Au, Pt and Al, with Au being the most preferred metal. Themodified surface region may include the surface of the membrane region,the surface of the respective electrode, or both.

[0017] The control means comprises an actuator utility (either a commonoscillator for all the crystal resonators or a plurality of oscillatorseach associated with a corresponding one of crystal resonators, and oneor more switches depending on the number of crystal resonators) and adetector utility. The actuator utility actuates said at least onecrystal resonator to put it in operation. The detector utility comprisesan electronic circuit for detecting the frequency of the at least onecrystal resonator to enable measurement of said change.

[0018] According to yet another aspect of the present invention, thereis provided a piezoelectric sensor device for identifying at least oneforeign material from environment, the device comprising:

[0019] (i) a sensor including a piezoelectric crystal element having atleast one piezoelectric crystal resonator in the form of an invertedmesa structure defining a sensing membrane-like region, which issubstantially thinner as compared to end portion of the crystalresonator surrounding said membrane-like region and has a certainresonance frequency value, and having electrodes formed on oppositesides of said sensing membrane-like region, said at least one crystalresonator having a surface region modified with molecules capable ofinteracting with a foreign material of the environment to yield areaction product that effects a change in the resonance frequency ofsaid at least one membrane-like region from said certain resonancefrequency value, said change being indicative of the identity andquantity of said foreign material; and

[0020] (ii) a control means operable for actuating said at least onecrystal resonator, measuring the change in the resonance frequency, andgenerating measured data representative of the identity and quantity ofsaid foreign material.

[0021] Preferably, the crystal element comprises an array ofspaced-apart crystal resonators, each in the form of the inverted mesastructure formed with a pair of electrodes at opposite surfaces of themembrane-like region, thereby defining an array of sensing regionsaffectable by the environment. The surface regions of different crystalresonators are modified with different reactive molecules, therebyenabling the detection of various foreign materials contained in theenvironment. Au electrodes, for example, are suitable for modificationwith sulfa containing molecules. When the quartz membrane regionparticipates in the sensing operation, then the quartz may be modifiedby different functional groups, such as, for example, silanes.

[0022] The crystal element may comprise the so-called “reference” or“passive” crystal resonator (without coating) which is screened from theenvironment. The change of the resonance frequency of the “active”crystal resonator caused by the foreign material is thus determined as adifference between the resonance frequencies of the active and passiveelements. Alternatively, such reference data (or the certain value ofthe resonance frequency characterizing the crystal resonator) may bestored in a memory of the control means.

[0023] Preferably, the crystal resonators are equally distanced from theactuator utility (oscillator). This may be implemented by arranging theresonators (wherein one of the crystal resonators may be the referenceor passive element) in spaced-apart relationship along a circular pathand placing the common oscillator either in the center of the circle orat any other location at the central axis of the circle. Thus, thecrystal element may comprise a disc carrying the circular array of theequally spaced piezoelectric crystal resonators, and the actuatorutility located on the central axis of the disc. It should be understoodthat the entire disc may be made of a piezoelectric crystal, in whichcase the crystal is patterned to define the circular array ofspaced-apart inverted mesa structures (i.e., the circular array ofmembrane-like regions defining the sensing regions). In another examplesof the invention, the plurality of oscillators are placed on the disccarrying the plurality of crystal resonators, and all the crystalresonators are equally distanced from their respective oscillators.

[0024] According to yet another aspect of the present invention, thereis provided a piezoelectric sensor device for identifying at least oneforeign material from environment, the sensor device comprising:

[0025] an array of spaced-apart crystal resonators, each crystalresonator being in the form of an inverted mesa structure having amembrane-like region, which is substantially thinner as compared to endportion of the crystal resonator surrounding said membrane-like regionand has a certain resonance frequency value, each of the crystalresonators being excitable by the environment to cause a change in theresonance frequency thereof from said certain resonance frequency value;and

[0026] an actuator utility for operating the crystal resonators, saidactuator utility being arranged such that each of the crystal resonatorsis spaced the same distance from its associated oscillator of theactuator utility.

[0027] The modification of the surface region of the crystal resonatormay be achieved by two alternative techniques: (1) construction oforganized, self assembled monolayers (SAM); or (2) formation ofpolymeric layer.

[0028] The organized, self-assembled monolayer (SAM) consists ofreceptor compound comprising a linker that connects said compound to thesurface of said substrate, an optional spacer, a structural element andan active head group.

[0029] Relating to the formation of a polymeric layer, the preferredtechnology for forming a polymer layer in a controlled manner is byelectropolymerization.

[0030] It should be noted that the device of the present invention couldbe used in gaseous medium, liquid medium or a combination thereof, thusacting as an electronic nose and/or as an electronic tongue. Anelectronic tongue is a device similar to the electronic nose, butcapable of operating in a liquid medium, and enables the analysis ofsolutes in a solution. Such a combined device provides for simultaneousanalysis of a solution and it's vapors, providing a complete picture ofthe detected material.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to understand the invention and to see how it may becarried out in practice, a preferred embodiment will now be described,by way of non-limiting example only, with reference to the accompanyingdrawings, in which:

[0032]FIGS. 1A and 1B are schematic illustrations of two examples of asensor device according to the invention;

[0033]FIGS. 2A to 2C more specifically illustrate a crystal resonator ina piezoelectric crystal element of the device of either of FIGS. 1A and1B;

[0034]FIGS. 3A to 3C illustrate experimental results of the absorptionof three different analytes: musk in ethanol, TATP and TNT;

[0035]FIGS. 4A and 4B are block diagrams of the devices of FIGS. 1A and1B, respectively, showing more specifically a control means of thedevice; and

[0036]FIG. 5 schematically demonstrates the principles of modificationof the metal surface of an electrode in the crystal resonator of eitherone of FIGS. 2A and 2B by utilizing the construction of organized,self-assembled monolayers (SAM).

DETAILED DESCRIPTION OF THE INVENTION

[0037] Referring to FIG. 1A, there is illustrated a sensor device 10Aaccording to the invention, which, in the present example, isimplemented as a disc-shaped printed circuit board 12. The device 10comprises such main constructional parts as sensor comprising apiezoelectric crystal element (quartz crystal in the present example),and a control means.

[0038] The crystal element may comprise one or more crystal resonators,eight such resonators CE₁-CE₈ made of quartz crystal being shown in thepresent example. The control means comprises electronic components,which are incorporated in the disc 12 and include an actuator utility14A, and a detector utility, generally at 15. The actuator utility 14Ais composed of an oscillator, and a plurality of switches associatedwith the crystal resonators, respectively, as will be described morespecifically further below with reference to FIG. 4A.

[0039] The quart crystal resonators CE₁-CE₈ are arranged in aspaced-apart relationship along a circular path centered around theactuator utility 14A. This arrangement equally distances all the quartzcrystal resonators from the oscillator. It should be understood that thesame can be achieved by placing the oscillator at any location on thecentral axis of the circle formed by the array of equally spaced quartzcrystal resonators.

[0040] It should be noted, although not specifically shown, that one ofthe crystal resonators may be a reference one screened from theenvironment, to which the other “active” resonators are exposed. Theprovision of such a reference crystal resonator is optional, and may bereplaced by the storage of a reference signal in a memory of the controlmeans.

[0041]FIG. 1B exemplifies a sensor device 10B according to theinvention. To facilitate understanding, the same reference numbers areused to identify the common components in the devices 10A and 10B. Thedevice 10B thus differs from the device 10A in the construction of anactuator utility 14B, which utilizes several oscillators—eightoscillators OS₁-OS₈ in the present example each associated with acorresponding one of eight crystal resonators CE₁-CE₈. Separateoperation of each crystal resonator by its associated oscillator allowsfor increasing the number of crystal resonators in the matrix(practically with no limitations for the number of crystal resonators).Here, similar to the device 10A, the symmetry of accommodation of thecrystal resonators is maintained, i.e., each of the crystal resonatorsis spaced the same distance from the respective oscillator.

[0042] Turning now to FIGS. 2A-2C, each of the quartz crystal resonatorsis an inverted mesa structure 16 defining a membrane-like region 18having a thickness of about several micrometers. To fabricate such aninverted mesa structure, a crystal is patterned either at one sidethereof to form one recess (FIG. 2A), or at both opposite sides thereofto form two opposite recesses (FIG. 2B), thereby forming the membranecentral region 18 of a sufficiently small thickness (to obtain desirablyhigh sensitivity of the sensor device) between two relatively thickerend portions of the structure surrounding the membrane-like region.Metal electrodes 20A and 20B (made from Al, Pt or Au) are deposited ontoopposite surfaces of the membrane-like region 18. As shown in theexample of FIG. 2C (illustrating a crystal element with a singleresonator), the crystal element is supported by a holder 21. Preferably,Au-based glue is used for attaching the crystal element to the holder.

[0043] The active quartz crystal resonator is formed with a surfaceregion 22 (exposed to the environment) modified by reacting moleculesintended to interact with one or more specific foreign materials thatmay be present in the environment. In the present example, this isimplemented by coating the electrodes 20A and 20B with such a molecule,as will be described more specifically further below. It should,however, be noted that, generally, such a modified surface region mayinclude the surface of the electrodes (or only one electrode located onthat side of the device by which it is exposed to environment), thesurface of the membrane-like region, or both. An interaction betweenthese molecules and one or more specific foreign material affects thefrequency of vibration of the crystal resonator to change from thecertain resonance frequency value. This change is detected by thecorresponding electronic component of the control means.

[0044] As indicated above, the principle of the detection is that thefrequency of vibration of an oscillating crystal is decreased by theadsorption of a foreign material on its surface. A foreign material, forexample a gaseous pollutant is selectively adsorbed by the coating (onthe crystal surface or/and on the metal electrode surface coating thecrystal surface), thereby increasing the weight of the crystal aiddecreasing the frequency of vibration. The decrease in the frequency ΔF(Hz) of the crystal resonator is proportional to the increase in itsweight due to the presence of foreign material absorbed on the coatingand is represented by the following equation: ΔF=K·Δm, where Δm is thechange in mass per unit surface area and K is a constant which refers tothe basic frequency of the piezoelectric crystal plate.

[0045] It should be understood that what is actually detected by thedevice of the present invention utilizing several crystal resonators isthe so-called “electronic image” or pattern of the intensities and shapeof response of each of the crystal resonators in the crystal element.These responses are indicative of the decay of the vibrating frequenciesof the crystal resonators caused by the absorption of foreign materials.FIGS. 3A to 3C illustrate experimental results in the form of threedifferent measured patterns (electronic images), respectively, of theabsorption of three different analytes: musk oil in ethanol, TATP andTNT.

[0046]FIG. 4A illustrates a block diagram of the sensor device 10A,showing the main components of the control means 30A for operating andprocessing the response of (n−1) active quartz crystal resonatorsCE₂-CE_(n) utilizing a reference (passive) quartz crystal resonator CE₁.The actuator utility 14A of the control means 30A comprises n switches,which, by n input ports thereof, are connected to the n quartz crystalresonators CE₁-CE_(n), respectively, and by the output ports thereof,are connected to the input port of an oscillator OS. The switches, byother input ports thereof, are connected to a pulse distributor 31. Theoscillator's output is connected to one input port of a double balancedmixer 32, the other input port of the mixer 32 being connected to theoutput port of a reference oscillator 34. The output port of the doublebalanced mixer 32 is connected to the input of a band-pass filter 36,whose output port is connected to the input of a level converter 38,which, in turn, is connected by its output port to the input of afrequency meter 40. All the outputs of the frequency meter 40 areconnected to the respective inputs of a frequency decoder matter fixingdevice 42. The other input ports of the device 42 are connected tocorresponding output ports of a synchronizing and control circuit 44,whose output ports are connected to the inputs of the pulse distributor31.

[0047]FIG. 4B illustrates a block diagram of the sensor device 10Bshowing the main components of the control means 30B. Similarly, tofacilitate understanding, the common components in the control means 30Aof FIGS. 4A and 30B of FIG. 4B are identified by the same referencenumbers. As shown, the control means 30B utilize the actuator utility14B including n oscillators OS₁-OS_(n), each associated with acorresponding one of the crystal resonators CE₁-CE_(n).

[0048] The operation of the sensor device 10A (or 10B) is based on thecreation of an electronic image of a certain foreign material and theidentification of this material by means of neural network algorithmsutilizing an image processing (pattern recognition) technique. Theelectronic image of a foreign material is created by measuring andanalyzing the relative change of frequency of each quartz crystalresonator (i.e., membrane-like region) during the period of creation ofthe electronic image, as a combination of data generated by all quartzcrystal resonators. The relative frequency change of each quartz crystalresonator corresponds to the changes of various conditions affecting theresonator. As described above, the frequency of the quartz crystalresonator is affected by the presence of a foreign material, as well asby changes in the environmental parameters. In order to reduce theeffects of the environmental parameters up to a minimal value, thereference resonator CE₁, which is insensitive to the foreign material,is used.

[0049] The time period of the electronic image creation is defined bythe synchronizing and control circuit 44. The electronic image iscomposed of a preset number of information packages, each packageincluding a given number of measurement cycles. Each cycle is defined bythe pulse distributor 31, by means of sequential connection of theresonators CE₁-CE_(n) to the oscillator OS through the respectiveswitches (FIG. 4A), by switching of oscillators OS₁-OS_(n) via switches(FIG. 4B) or connecting the outputs of the oscillators OS₁-OS_(n) to theinput of the double balanced mixer 32 via respective switches (FIG. 4B).

[0050] When the quartz crystal resonator is connected to the oscillator,the latter is excited at the resonance frequency of the resonator, andthe oscillator generates a corresponding signal. This signal inputs thedouble balanced mixer 32, which also receives a reference signal fromthe reference oscillator 34. The use of the mixer 32 enables to extracta signal of the relative frequency change, while keeping the parametersand the frequency changes profile unchanged, thereby enabling to reducethe measurement time and increase the accuracy of the sensor device. Theband-pass filter 36 reduces the level of effects caused by theconversion up to a required value. An output signal of the filter 36 issupplied to frequency meter 40 through the level converter 38. Thecircuit 40 carried out frequency measurement, and a signalrepresentative of a measured frequency value, simultaneously withinformation about the number of the respective quartz crystal resonator,cycle and package for the data formation supplied from the synchronizingand control circuit 44, enter the device 42. When the time of theelectronic image formation expires, the information packages aremathematically processed, the foreign material is identified and anoutput signal indicative thereof is generated, being appropriatelyformatted in accordance with the user requirements.

[0051] The following table presents experimental results showing the gassensor sensitivity of various crystal resonators characterized bydifferent quartz crystal frequencies due to different values of themembrane thickness. Frequency (MHz) 9 30 150 250 300 500 MembraneThickness 185 56 11 6.7 5.6 3.3 (μm) Sensitivity (g) 1 × 10⁻⁹ 9.7 ×10⁻¹¹ 1.5 × 10⁻¹³ 2.2 × 10⁻¹⁴ 2.4 × 10⁻¹⁵ 4.2 × 10⁻¹⁶

[0052] The modification of the metal surface of the electrode may beachieved by two alternative techniques: (1) construction of organized,self assembled monolayers (SAM); or (2) formation of polymeric layer.These techniques are described hereinbelow:

[0053] (1) Construction of Organized SAM

[0054] The use of a piezoelectric substance such as quartz crystalscovered at least partially with a metallic electrode (either gold,platinum or aluminum) provides an essential tool for the construction oforganized organic monolayers. This is so due to the presence of anorganized metallic layer that chemically differs from its surroundingenables the selective modification of that part with a suitablefunctional group. A gold or platinum electrode, for example, can bemodified by sulfur containing molecules such as thiols, disulfides(either linear or cyclic) or thioethers. Aluminum electrodes can bemodified by acidic moieties such as carboxylic acids and sulfonic acids.

[0055] The concept of SAM allows us to prepare tailor made organicmolecules designed to act as artificial receptors, each bindingselectively to an analyte to be detected. However, it is important tonote that the artificial receptors are designed such that theirinteractions with an analyte are of moderate strength, leading to areversible interaction (i.e. interaction that will enable to use thedetector more than once). The artificial receptor according to thepresent invention comprises a linker that connects the receptor to thesurface of the electrode and/or of the crystal resonator, an optionalspacer, a structural element (the structural element and the optionalspacer determine the 3D structure and length of the whole monolayer) andan active head group. This arrangement is schematically demonstrated inFIG. 5 for a selective receptor molecule prepared on the surface of anelectrode.

[0056] Such a modular design is the basis for an united arsenal ofsurface modifications.

[0057] The linker is the element that connects the selective receptormolecule to the surface of the electrode and/or the resonator andcontrols the coverage and smoothness of the monolayer. When the quartzresonators are used with a gold electrode, the linker is based onsulfur-containing compounds, for example thioethers, disulfides orthiols.

[0058] When a spacer is included in the receptor molecules, it mayfulfil one or more of the following roles:

[0059] (i) To solve synthetic problems of connecting moieties that donot fit by means of functional groups. This is done by usingbifunctional spacers such as bromo-acids, diamines etc.

[0060] (ii) To control the flexibility of the molecule.

[0061] (iii) To introduce some chiral discrimination when a chiralspacer is used.

[0062] The structural elements are based on molecules which promote thestrong packing of the layers. Examples of such molecules are aromaticmolecules, e.g. phenyl, naphthyl or larger rings, that may be optionallysubstituted by at least one substituent, or amino acids optionallysubstituted that might stabilize the monolayer through hydrogen bonds.The substituents may be of various structures, e.g. electron withdrawingor electron donating groups, depending on the characteristics of theforeign substance to be detected.

[0063] The head groups may interact with a specific foreign substance byvarious mechanisms, for example by forming a chemical bond or bycreating a transition state resulting from weak interactions betweencompatible moieties, depending on the characteristics of the substanceand the head group. Examples of head groups are amino, nitro, hydroxyl,thio, thiol, carboxyl and carboxyl derivatives.

[0064] Examples of chemical reactions are between functional groups suchas carbazido groups and ketones to form Schiff bases (imines) or betweenboronic acids and diols to form boronic esters.

[0065] Except for the functional groups, the head group may also bearvarious substituents that affect the electron density of this element,thus altering the strength of the chemical bond or interaction betweenthe monolayer and the substance to be detected.

[0066] Several groups of artificial receptors with varying head groupshave been prepared:

[0067] The following compounds are novel and constitute a further aspectof the invention:

[0068] The above compounds may be prepared by known synthetic routes.For example, the compounds of Group D (when, q=0, X═O, R⁴═N(CH₃)₂) maybe prepared by two alternative synthetic pathways (Method I and MethodII) as follows:

[0069] The electronic nose of the invention has potential use for thedetection of hidden explosives. The chemical structures of someimportant explosives that are widely used by terrorists, including TATP(triacetone triperoxide) are shown hereinbelow:

[0070] (2) Formation of Polymeric Layer

[0071] As already mentioned above, the modification of the metallicsurface of the electrode can be achieved by two alternative ways, by SAMformation or by polymeric layer formation. Relating to the formation ofa polymeric layer, the preferred technology for forming a polymer layeron a metallic surface in a controlled manner is byelectropolymerization.

[0072] The following polymeric layers were produced and examined foradsorbing explosives: polypyrrole, polythiophene, polytriphenylene,poly(dimethylamino)pyrrole, polypyrene, polyfluorene, polyfluoranthene,polyaniline, poly(N-phenyl)aniline, poly(N-methyl)aniline andpolyfluoroaniline.

[0073] The present invention is now described by the followingnon-limiting examples:

EXAMPLES Example 1 General Procedure for the Preparation of a Monolayer

[0074] A quartz crystal resonator provided with a pair of goldelectrodes on both surfaces thereof was treated with a solution of ansulfur molecule (0.1 nM in absolute ethanol) for 12 hours at 60° C. Theresonator was then soaked for 30 min in ethanol, first at 60° C. andthen at 30° C., afterwards in acetone for 20 min. at 30° C. threeconsequent times and dried at 60° C. for 1 hour. The thickness of thereactive monolayer formed is estimated by the change of the resonatorfrequency, considering also other parameters such as the electrodediameter and the quartz' density. The practically used equation for 300MHz resonators is as follows:${\Delta \quad h} = \frac{{- \Delta}\quad f}{{{- 2.07} \cdot 10^{11}}\rho}$

[0075] where Δh is the thickness of coating (Å); Δf is the difference infrequency (Hz) (coated vs. uncoated); ρ is the density of coating(g/cm³), and the coefficient (−2.07.10¹¹) presents the effect of theelectrode diameter and the quartz' density. The value of ρ is estimatedto be 1.3 (according to literature).

Example 2 Preparation of Polyaniline on Quartz Resonator

[0076] A thin layer of polyaniline on quartz resonator provided withgold electrodes was prepared by two alternative methods:

[0077] 1. By electropolymerization of an aqueous solution of 0.1Maniline+1M methansulfonic acid, using a potential cycling at 0-0.85V(vs.Ag/AgCl, KCl sat.) range; followed by rinsing in water and drying at 60°c.

[0078] 2. By a two steps method: a) pretreatment of the resonator withan ethanolic solution of 0.001M 4-aminothiophenol for 18 hrs. at roomtemperature; followed by rinsing in ethanol and water, to form on theresonator surface a layer of 4-aminothiophenol; b) Electropolymerizationof the product obtained in step a) in an aqueous solution of 0.1Maniline+1M methansulfonic acid, using a potential cycling at 0-0.85V(vs.Ag/AgCl, KCl sat.) range; followed by rinsing in water and drying at 60°C.

[0079] In the second method the polymerization is carried out on apreformed layer of 4-aminothiophenol in order to increase the stabilityof the formed polymeric layer and its uniformity

Example 3 Synthesis of Compound (4)

[0080]

[0081] First Step:

[0082] Triphenylmethanethiol (1.148 g, 0.00415 mol) was dissolved in THF(25 ml dried over basic alumina). Freshly prepared 2N NaOMe (2.3 ml) wasadded and the reaction mixture was stirred for half an hour.1,3-Dibromo-2-propanol (0.19 ml, 0.0015, mol) was added and the reactionmixture was stirred for four hours at ambient temperature and thenbrought to reflux and heated for additional three hours. Aftercompletion of the reaction, hexane was added and the organic layer waswashed with aqueous methanol (30% methanol), dried over anhydrous sodiumsulfate, and concentrated. Flash chromatography withhexane:dichloromethane (6:4) as eluent afforded the product (1 g, 77%).

[0083] 1H NMR (250 MHz) δ ppm: 2.1 (d, 1H, J=4 Hz, CH(OH)), 2.3 (m, 4H,CH₂), 3.0 (m, 1H, CH(OH)), 7.4 (m, 30H, Ar).

[0084] Second Step:

[0085] 4-Dimethylamino benzoic acid (0.2 g, 0.0012 mol) was stirred withoxalyl chloride (1 ml, 0.012 mol) in dichloromethane (10 ml, dried overbasic alumina) with one drop of DMF at room temperature for 4 hours. Thesolvent was evaporated. The residue was dissolved in dichloromethane (20ml, dried over basic alumina) and the solution was brought to pH=8 withtriethyl amine.

[0086] Basic solution of 4-dimethylaminobenzoyl chloride was addeddropwise to the solution of 1,3-bis(triphenylmethanethio)-propane-2-ol(0.67 g, 0.0011 mol) in dichloromethane (10 ml, dried over basicalumina) with triethyl amine (0.2 ml, 0.0013 mol). The reaction mixturewas stirred at ambient temperature for 3 hours. Hexane (100 ml) wasadded to the reaction mixture. Organic layer was washed with aqueousmethanol (30% methanol), dried over sodium sulfate anhydrous, andconcentrated. Flash chromatography with hexane: dichloromethane (6:4)afforded the product (0.7 g, 84%).

[0087] 1H NMR (250 MHz) δ ppm: 2.4 (abddd, 4H, J₁=J₂=6.5 Hz, CH₂), 4.75(dd, 1H, CH) 6.7 (d, 2H, J=9 Hz, Ar), 7.4 (m, 30H, 2×C(Ph)₃), 7.9 (d,2H, J=9 Hz, Ar).

[0088] Third Step:

[0089] To the solution of 1,3-bis(triphenylthio)-propane-2-ol derivative(0.7 g, 0.0005 mol) in dichloromethane (5 ml), trifluoroacetic acid (1ml) was added. The reaction mixture was stirred for 4 hours at ambienttemperature. The solvent was evaporated. The crude was dissolved indichloromethane-methanol. Freshly prepared 2N sodium methylate (0.9 ml)was added followed by addition of iodine (0.47 g). Flash chromatographywith hexane:ethyl acetate (6:4) afforded compound 4 (0.19 g, 78%). 1HNMR (300 MHz) δ ppm: 3.0 (s, 6H, N(CH₃)₂), 3.4 & 3.6 (abddd, 4H, J₁=1.8Hz, J₂=8 Hz, J₃=62 Hz, CH₂), 5.8 (ddd, 1H, J=8 Hz, CH), 6.6 (d, 2H,J=9.1 Hz, Ar), 7.5 (d, 2H, J=9.1 Hz, Ar).

Example 4 Synthesis of Compound (5)

[0090]

[0091] First Step:

[0092] A suspension of sodium hydrogen sulfide (21 g, 0.375 mol) inmethanol (150 ml was prepared. Epichlorohydrine (5 ml, 0.065 mol) in THF(20 ml) was added dropwise at room temperature. The flask was sealed andthe reaction mixture was stirred overnight at room temperature. Methanolwas evaporated and the residue was dissolved in water (50 ml). Aqueouslayer was extracted with chloroform. Collected organic fractions weredried over sodium sulfate and concentrated. The residue was used forfurther step without purification.

[0093] Second Step:

[0094] To the solution of 4-hydroxy-1,2-dithiolane (as a crude from thereaction between epichlorhydrine and sodium hydrogen sulfide) (0.1 g) indichloromethane (dried over basic alumina 10 ml) toluoyl chloride (0.14ml, 0.001 mol) was added followed by addition of triethylamine (0.23 ml,0.0016 mol). The reaction mixture was stirred overnight at ambienttemperature. Flash chromatography with hexane-ethyl acetate (4:6) aseluent afforded compound 5 (15 mg).

[0095] 1H NMR (300 MHz) δ ppm: 2.4 (s, 3H, CH₃), 3.15 & 3.25 (abddd, 4H,J₁=3.8 Hz, J₂=7.2 Hz, J₃=15 Hz, CH₂), 5.8 (ddd, 1H, J₁=3.8 Hz, J₂=7.1Hz, CH), 7.2 (d, 2H, J=8.2 Hz, Ar), 7.9 (d, 2H, J=8.2 Hz, Ar).

Example 5 Synthesis of O-benzoyl [1,2] dithiolan-4-ol (6)

[0096]

[0097] Epichlorohydrin (3 ml, 0.029 m ol) was added to a solution ofNaSH (15 g, 0.27 mol) in MeOH (115 ml). The solution was stirred at roomtemperature over night. MeOH was evaporated, the residue was dissolvedin brine (i.e. saturated aqueous NaCl solution), extracted several timeswith chloroform, dried with sodium sulfate, filtered and evaporated todryness. The product 4-hydroxy-1,2-dithiolane was not purified forfurther reaction.

[0098] Benzoyl chloride (1.4 ml) and triethyl amine (1.2 nm) were addedto a solution of 4-hydroxy-1,2-dithiolane (as a crude from the reactionbetween epichlorhydrine and sodium hydrogen sulfide) (1 gr) in drydichloromethane (30 ml). The solution was stirred at room temperatureunder nitrogen over night. Dichloromethane was added to the solution,extracted several time with aqueous K₂CO₃ 5%, HCl 1N and Brine, driedover sodium sulfate, filtered and evaporated to dryness.

[0099] The product obtained was purified by a flash columnchromatography of Silica gel with dichloromethane:hexane (2:1) as eluentto give compound 6 (0.25 gr.); NMR (CDCl₃, 250 MHz) δ=8.03(m, 2H, Arm),7.58(m, 1H, Arp), 7.43(m, 2H, Ar_(o)), 5.48(m, 1H, SCH₂CHO), 3.21(m, 4H,SCH₁₂CHO); IR (CHCl₃) v=1734 cm⁻¹ (ester).

Example 6 Synthesis of Compound (7)

[0100]

[0101] First Step:

[0102] (according to the procedure in Becker H. J., Tamsma A. F, Rec.Trav. Chim, 1938, 1183-1210).

[0103] A suspension of sodium hydrogen sulfide (10.7 g, 0.19 mol) inmethanol (100 ml) was prepared. 2,2-Bis(bromomethyl)-1,3-propanediol (5g, 0.019 mol) in methanol (20 ml) was added dropwise at roomtemperature. The flask was sealed and the reaction mixture was stirredfor 18 hours at room temperature and then refluxed for 2 additionalhours. One third of methanol was evaporated and ethyl acetate was added(50 ml). The precipitate was filtered out and the procedure was repeatedfour times with supernatant. Ethyl acetate was evaporated.Recrystalization from hot toluene afforded the product (1.6 g; 50%).

[0104] 1H NMR (250 MHz, CD₃OD) 5 ppm: 2.9 (s, 2H, CH₂S), 3.6 (s, 2H,CH₂O).

[0105] Second Step:

[0106] To the solution of 4,4-bis(hydroxymethyl)-1,2-dithiolane (0.15 g,0.0009 mol) in dichloromethane (dried over basic alumina 10 ml) benzoylchloride (0.23 ml, 0.002 mol) was added followed by addition oftriethylamine (0.29 ml, 0.002 mol). The reaction mixture was stirredovernight at ambient temperature. Flash chromatography withhexane-chloroform (6:4) as eluent afforded the product (120 mg, 35%).

[0107] 1H NMR (300 MHz, CDCl₃) δ ppm: 3.2 (s, 2H, CH₂S), 4.5 (s, 2H,CH₂O), 7.4 (dd, 2H, J₁=J₂=7.8 Hz, Ar), 7.55 (dd, 1H, J₁-J₂=7.8 Hz, Ar),8.0 (d, 2H, J=7.8 Hz).

Example 7 Synthesis of thioether carbazido Compound (8)

[0108] The compound was synthesized via the following pathway:

[0109] First Step: Synthesis of I:

[0110] Anhydrous potassium carbonate was added to a solution of2-methyl-1-butanethiol in DMF. Bromo-ethylbutyrate was added and stirredover night.

[0111] The solution was dissolved in a mixture of hexane/ethyl acetate(1:3) and washed several times with water, dried over Na₂SO₄, filteredand evaporated to dryness. The product I may contain traces of thethiol.

[0112] Second Step: Synthesis of II:

[0113] The ester I was dissolved in MeOH (10 ml/mmol) and 1N NaOH (1.11ml) and stirred for 1 hour. In a case that the reaction was not ended,additional aliquot of NaOH was added. After the consumption of theester, MeOH was evaporated, the residue was dissolved in water andwashed with EtOAc. The basic aqueous solution was acidified with KHSO₄1M to pH 4. The product was extracted several times with EtOAc, driedover Na₂SO₄, filtered and evaporated to dryness. The overall yield ofthe two steps is close to quantitative.

[0114] NMR (CDCl₃, 250 MHz) δ=2.5 (m, 611 three methylene groups), 1.85(m, 2H, SCH₂CH₂CH₂), 1.47 (m, 2H, CH₃CH₂CH(CH₃)), 1.18 (m, 1H,CH₃CH₂CH(CH₃)), 0.94 (d, J=6.5H, 31, CH₃CH₂CH(CH₃)), 0.87(d, J=7 Hz, 3H,CH₃CH₂CH(CH₃)). IR (CHCl₃) v=1715 cm⁻¹ (COOH).

[0115] Third Step: Synthesis of III:

[0116] Oxalyl chloride (4.5 ml) and a few drops of DMF were added to asolution of the acid II (1.6 gr.) in dry dichloromethane and kept underinert atmosphere over night. The solvents were removed in vacuo, theresidue was dissolved in dry dichloromethane and introduced in adropping funnel under nitrogen stream. The acyl chloride was addeddropwise to a solution of p-phenylene diamine in DMF (3.5 ml in 15 mlDMF) and the mixture was stirred for two hours. Chloroform was added andthe organic solution was washed with water and dried. The product waspurified by flash column chromatography (chloroform: MeOH 95:5 aseluent) to give pure product. (900 mg, 40%). NMR (CDCl₃, 250 MHz)δ=7.5(b, 1H, CONHAr), 7.25+6.6 (Abq, 4H, Ax) 2.5 (m, 6H, three methylenegroups), 1.95 (m, 2H, SCH₂CH₂CH₂), 1.5 (m, 2H, CH₃CH₂CH(CH₃)), 1.2 (m,1H, CH₃CH₂CH(CH₃)), 0.94 (d, J=6.5 Hz, 3H, CH₃CH₂CH(CH₃)), 0.87(d, J=7Hz, 3H, CH₃CH₂CH(CH₃)). IR (CHCl₃) v 1670 cm⁻¹ (CONH).

[0117] Fourth Step: Synthesis of IV:

[0118] Triphosgene (400 mg.) and 2,6 lutidine (1 ml) were added to asolution of the free amine III (900 mg) in dry dichloromethane underinert atmosphere and stirred for 10 min. t-Bu-carbazate (500 mg) wasadded and the mixture was left for an hour. Chloroform was added and theorganic solution was washed with NaHCO₃ 1N, HCl 1N, water and dried. Theproduct was purified by flash column chromatography (chloroform:MeOH95:5 as eluent) to give 700 mg almost pure product IV. The product wasrecrystalized from MeOH/ether to give of pure IV (500 mg., 35%). NMR(CDCl₃, 250 MHz) δ=8.27 (b, 1H, NHNHBoc), 7.79 (b, 1H, NHNHBoc), 7.4 (b,1H, CONHAr), 7.7 (in, 4H, Ar), 2.5 (in, 6H, three methylene groups),1.98 (m, 2H, SCH₂CH₂CH₂), 1.5 (m, 1H, Boc+CH₃CH₂CH(CH₃)), 1.2 (m, 1H,CH₃CH₂CH(CH₃)), 0.97 (d, J=6.5 Hz, 3H, CH₃CH₂CH(CH₃)), 0.88(d, 3=7 Hz,3H, CH₃CH₂CH(CH₃)). IR (CHCl₃)) V 1670 cm⁻¹ (CONH), 1710 cm⁻¹ (Boc).

[0119] Last Step: Synthesis of 8:

[0120] The boc-protected semicarbazide IV (160 mg.) prepared above wastreated with 15% TFA in dichloromethane over night, the solvent wasremoved, the residue was treated with triethylamine (in methanol) toobtain neutral pH, dried, and purified by flash column chromatography(chloroform:MeOH 95:5 as eluent) to give of product 8. (100 mg, 80%).

[0121] NMR (MeOD+CDCl₃, 250 MHz) δ=7.4 (m, 4H, Ar), 2.45 (m, 6H, threemethylene groups), 1.92 (m, 2H, SCH₂CH₂CH₂), 1.4 (m, 2H, CH₃CH₂CH(CH₃)),1.1 (m, 1H, CH₃CH₂CH(CH₃)), 0.89 (d, J=6.5 Hz, 3H, CH₃CH₂CH(CH₃)), 0.83(d, 3=7 Hz, 3H, CH₃CH₂CH(CH₃)).

Example 8 Synthesis of acetanilide Derivatives 9 and 10

[0122] The acetanilide derivatives 9 and 10 were synthesized in athree-step procedure, as showed below:

[0123] Compound 9: R═(CH₂)₇CH₃, n=2

[0124] The first two steps are identical to those of the synthesis ofcompound 8. Oxalyl chloride (5 ml) and a few drops of DMF were added toa solution of the acid VI (0.8 gr.) in dry dichloromethane and keptunder inert atmosphere over night. The solvents were removed in vacuo,the residue was dissolved in dry dichloromethane. p-Amino acetanilide(0.8 gr.) and triethylamine (1 ml) were added to the solution andstirred at room temperature for additional 3 hours. The solution waswashed with HCl 1N and aqueous K₂CO₃ (5%), dried over MgSO₄ followed bycolumn purification (chloroform: ethyl acetate 1:1 as eluent) to providepure compound 9. (400 mg., 31%)

[0125] NMR (CDCl₃, 250 MHz) δ=7.58 (b, 1H, NH), 7.45 (s, 4H, Ar), 7.17(b, 1H, NH), 2.89 (t, J=7 Hz, 2H, CH₂CO) 2.56 (m, 4×, CH₂SCH₂), 2.17 (s,3H, COCH₃), 1.25 (m, 12H, CH₃(CH₂)₆(CH₂), 0.87 (bt, 3H, CH₃(CH₂)₆CH₂).

[0126] Synthesis of Compound (10): R═(CH₂)₃CH₃, n=3

[0127] The first two steps are identical to those of the synthesis ofcompound 8. Oxalyl chloride (10 ml) and a few drops of DMF were added toa solution of the acid VI (2.6 gr.) in dry dichloromethane and keptunder inert atmosphere over night. The solvents were removed in vacuo,the residue was dissolved in dry dichloromethane. p-Amino acetanilide (2gr.) and triethylamine (2 ml) were added to the solution and stirred atroom temperature for additional 3 hour. The solution was washed with HCl1N and aqueous K₂CO₃ (5%), dried over MgSO₄ followed by columnpurification (metlylene chloride:ethyl acetate 1:1 as eluent) to providepure compound 10. (800 mg., 18%)

[0128] NMR (CDCl₃, 250 MHz) δ=7.46 (s, 4H, Ar), 7.25 (b, 1H, NH), 7.15(b, 1H, NH), 2.60 (t, J=7 Hz, 2H, CH₂CO) 2.5 (m, 4H, CH₂SCH₂), 2.17 (s,3H, COCH₃), 2.05 (m, 2H, CH₂CH₂CO), 1.42 (m, 4H, CH₃(C₁H₂)₂CH₂), 0.91(t, J=7 Hz, 3H, CH₃(CH₂)₂CH₂).

Example 9 Affinity and Selectivity Experiments

[0129] The following receptor molecules have been tested:

[0130] The affinity and selectivity of the receptors 4-10 and of a fewpolymeric receptors were examined in the following way:

[0131] i—A 250 MHz quartz crystal resonator was first modified with amonolayer comprising one of the artificial receptors 4-10.

[0132] ii—Three analytes were checked: TATP, Naphthalene and2,3-dimethyl-2,3-dinitrobutane, each having a specific vapor pressure.

[0133] iii—The frequency change of the resonator due to the exposure tothe vapor of ˜100 μg of the analyte at room temperature in a 2 ccchamber was recorded within 60 sec.

[0134] The following table summarizes the maximum response (measured inHz) of some modified resonators to the tested analytes: Compound TATPNaphthalene DDB 4 1370 2500 380 5 720 700 230 6 6950 1900 250 7 47502520 300 8 300 1000 80 9 650 1080 230 10  4200 1350 780 Polyfluorene1100 2100 420 Polypyrrole 1500 2900 320 Poly (N-methyl 1300 1950 130aniline)

Example 10 Detection of Iohexole in Liquid Environment

[0135] The boronic acid derivative 11 synthesized for the detection ofiohexole in solution has the following structure:

[0136] Iohexole is a compound used as a source for iodine needed for CTscans. However, the secretion of iohexole in the urine may also indicatecertain gastro diseases.

[0137] The boronic acid derivative was prepared according to thefollowing scheme:

[0138] a) Synthesis of p-bromomethyl phenyl boronic acid—neopentyl ester(VII and VIII)

[0139] (according to the procedure in Nakao H. et al. Biosci. Biotech.Biochem 60(4) 1996, 683-684.)

[0140] p-Toluene boronic acid (750 mg.) and neopentyl glycol (600 mg.)were dissolved in 50 ml cyclohexane and heated at reflux for 1.5 hours.N-Bromosuccinimide (1.15 g.), benzoyl peroxide (25 mg.) and 150 mlcyclohexane were added and the solution was heated at reflux foradditional 2 hours. The solution was cooled to room temperature,filtered and evaporated to give a mixture of VII and VIM (total of 1.3g,˜1:1 ratio), the yield=47%. NMR (CDCl₃, 250 MHz) δ=7.81+7.38 (Abq, 4H,Ar), 5.50 (s, 2H, ArCH₂Br), 3.77 (s, 4H, OCH₂C), 1.03 (s, 6H, C(CH₃)₂).

[0141] b) Synthesis of I:

[0142] Anhydrous potassium carbonate was added to a solution of1-butanethiol (90 μl) in DMF. A (450 mg.) was added and the mixture wasstirred over night.

[0143] The solution was dissolved in a mixture of hexane/ethyl acetate(1:3) and washed several times with water, dried over Na₂SO₄, filteredand evaporated to dryness. The product was purified by flash columnchromatography (ethyl acetate: dichloromethane 4:6 as eluent).Yield=15%.

[0144] NMR (CDCl₃, 250 MHz) δ=7.72+7.27 (Abq, 4H, Ar), 3.74 (s, 4H,OCH₂C), 3.68 (s, 2H, ArCH₂S) 2.40 (m, 2H, SCH₂CH₂CH₂CH₃), 1.54 (m, 2H,SCH₂CH₂CH₂CH₃), 1.31 (m, 2H, SCH₂CH₂CH₂CH₃), (m 1.00 (s, 6H, C(CH₃)₂),0.85 (t, J=7 Hz, 3H, SCH₂CH₂CH₂CH₃).

[0145] c) Synthesis of 11

[0146] The boronic ester IX (50 mg.) was hydrolyzed in THF/HCl 2N (1:1)over night at room temperature. The THF was evaporated, the residue wasdissolved in ethyl acetate, washed with water and purified by threeconsequence chromatography columns ((i) CHCl₃:MeOH 97:3, (ii) CHCl₃:MeOH99:1, n-Hexane:Ethyl acetate (gradient from 20% to 50% ethyl acetate)).Yield=15%. NMR (CDCl₃, 250 MHz) δ=7.20+6.73 (Abq, 4H, Ar), 3.65 (s, 2H,ArCH₂S) 2.43 (m, 2H, SCH₂CH₂CH₂CH₃), 1.28 (m, 4H, SCH₂CH₂CH₂CH₃), 0.88(t, J=7 Hz, 3H, SCH₂CH₂CH₂CH₃).

[0147] Measurements were performed with 30 MHz resonators in water. Theresponse of a resonator coated with the boronic acid derivative 11, indistilled water, was compared to that of a 25 μg/ml solution of iohexoleas an analyte.

[0148] The response of the resonator to the iohexole solution was in therange of 600 Hz.

[0149] Those skilled in the art will readily appreciate that variousmodification and changes can be applied to the embodiments of theinvention as hereinbefore described and exemplified without departingfrom its scope defined in and by appended claims.

1. A piezoelectric crystal element for use in a sensor device for identifying at least one foreign material from environment, the crystal element comprising at least one crystal resonator in the form of an inverted mesa structure having a membrane-like region, which is substantially thinner as compared to end portion of the crystal resonator surrounding said membrane-like region and has a certain resonance frequency value, a surface region of said at least one crystal resonator being modified by reactive molecules of a kind capable of interacting with said at least one foreign material to yield a reaction product that effects a change in the resonance frequency of said membrane-like region from said certain resonance frequency value, said change being indicative of the identity and quantity of said at least one foreign material.
 2. The element according to claim 1, wherein said at least one crystal resonator is a quartz crystal.
 3. The element according to claim 1, wherein said at least one membrane-like region has a thickness of about several micrometers.
 4. The element according to claim 1, wherein the membrane-like region of the at least one crystal resonator is coated with metal electrodes on opposite sides thereof, said electrodes being made of metal selected from Au, Pt and Al.
 5. The element according to claim 4, wherein said electrodes are made of Au.
 6. The element according to claim 4, wherein an Au-based glue is used for attaching the crystal element to a holder.
 7. The element according to claim 1, further comprising at least one additional crystal resonator in the form of an inverted mesa structure having a membrane-like region substantially thinner as compared to end portion of the additional crystal resonator surrounding said membrane-like region, and having a surface region modified by reactive molecules of a kind capable of interacting with a foreign material of the environment to yield a reaction product that effects a change in the resonance frequency of the additional membrane-like region.
 8. The element according to claim 7, comprising an array of spaced-apart crystal resonators, each resonator being in the form of an inverted mesa structure formed with a pair of electrodes at opposite sides of the membrane-like region thereof and having the modified surface region, thereby defining an array of sensing regions excitable by the environment to produce the changes in the frequencies of crystal resonators.
 9. The element according to claim 7, wherein the surface regions of different crystal resonators are modified with different reactive molecules, thereby enabling detection of various foreign materials contained in the environment.
 10. A piezoelectric sensor for use in a device for identifying at least one foreign material from environment, the piezoelectric sensor comprising the piezoelectric crystal element of any one of preceding claims with electrodes formed on opposite sides of said at least one membrane-like sensing region.
 11. A piezoelectric sensor device for identifying at least one foreign material from environment, the device comprising the sensor of claim 10, and a control means operable for actuating said at least one crystal resonator, measuring the change in the resonance frequency of said at least one membrane-like region, and generating measured data indicative of the identity and quantity of said at least one foreign material.
 12. The device according to claim 11, wherein the control means comprises an actuator utility for operating said at least one crystal resonator, and a detector utility for detecting the frequency of said at least one membrane-like region to enable the measurement of said change.
 13. The device according to claim 8, wherein a distance between each of the crystal resonators and its associated oscillator of the actuator utility is the same for all the crystal resonators.
 14. The device according to claim 13, wherein the crystal resonators are arranged in spaced-apart relationship along a circular path, and are associated with the common oscillator located on a central axis of the circle.
 15. The device according to claim 13, wherein the piezoelectric crystal element comprises a disc formed with a circular array of the piezoelectric quartz crystal resonators, and the actuator utility comprises the oscillator located in the center of the disc and associated with all the crystal resonators.
 16. The device according to claim 13, wherein the piezoelectric crystal element comprises a disc formed with a circular array of the piezoelectric quartz crystal resonators, and the actuator utility comprises a plurality of oscillators located on said disc, each of the oscillators being associated with a corresponding one of the oscillators.
 17. The piezoelectric crystal element according to claim 1, wherein said reactive molecules form an organized, self-assembled monolayer (SAM), said monolayer consisting of receptor compounds comprising a linker that connects said compound to the surface of said substrate, an optional spacer, a structural element and an active head group.
 18. The piezoelectric crystal element according to claim 1, wherein said surface region of said at least one crystal resonator is modified by a polymeric layer.
 19. The piezoelectric crystal element according to claim 18, wherein said polymeric layer comprises at least one polymeric material selected from the group consisting of: polypyrrole, polythiophene, polytriphenylene, poly(dimethylamino)pyrrole, polyaniline, poly(N-phenyl)aniline, poly(N-methyl)aniline, polyfluoroaniline, polypyrene, polyfluorene and polyfluoranthene.
 20. An organized, self-assembled monolayer (SAM) for use in a sensor device for identifying at least one foreign material from environment, said monolayer is to be formed on a surface of a sensing region of a crystal resonator, said monolayer consisting of receptor compound comprising a linker that connects said compound to the surface of said substrate, an optional spacer, a structural element and an active head group.
 21. A SAM according to claim 20, wherein said substrate includes at least one of the following: a metal electrode and a crystal's surface of a piezoelectric crystal resonator.
 22. A SAM according to claim 21, wherein said metal electrode is made of Au, Pt or Al.
 23. A SAM according to claim 21 formed on the surface of a gold electrode, wherein the linker of said receptor compound is made of sulfur containing molecule.
 24. A SAM according to claim 21, formed on the surface of an aluminum electrode, wherein the linker of said receptor molecule is made of carboxylic acid or sulfonic acid.
 25. A SAM according to claim 19, formed on the surface of a platinum electrode, wherein the linker of said receptor molecule is made of sulfur containing molecule.
 26. A SAM according to claim 22, further including a receptor compound for use in the formation thereof wherein said compound is a receptor compound selected from the following compounds:


27. A SAM according to claim 26, wherein said compound is selected from the following list of compounds:


28. (Canceled) 